Richard Stone, MD, on Updates in the Treatment of High-Risk AML

Richard M. Stone, MD, Chief of Staff, Director, Translational Research, Leukemia Division, Medical Oncology, Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School, Boston, Massachusetts, recently shared updates on the treatment of high-risk acute myeloid leukemia (AML) at the Second Summit of the Americas on Immunotherapies for Hematologic Malignancies.

Dr Stone said he typically divides patients with AML into good risk, intermediate risk, and high-risk, by focusing on gene fusion and certain mutations. High-risk AML typically includes patients with wild-type NPM1 and high FLT3-ITD ratio; inv(3); t(6;9) abnormalities of MLL rearrangements; and complex karyotypes, he said.

“I think high risk AML really is almost every patient with AML, because only about 15% have what we would consider favorable risk,” Dr Stone said.

According to him, AML patients with complex karyotypes do worse than those with TP53 mutations that do not have a complex karyotype.

“Obviously, P53 mutations are the absolute worst,” he added.

One way to treat high-risk AML, including those with therapy-related histories, history of mild-dysplasia beforehand, or mild-dysplasia related chromosomal abnormality, is to use CPX-351, a liposomal co-formulation of cytarabine and daunorubicin designed to achieve synergistic antileukemia activity.

“These liposomes stick around the bone marrow for a while, which could account for the efficacy of this drug,” Dr Stone said.

Referring to a randomized Phase 3 trial of CPX-351 versus 7+3 in older patients with secondary AML, Dr Stone said CPX-351 is “better than 7+3 in patients between 60 and 75 years of age who have a history of prior bone problems.”

The median survival in this trial was superior in the CPX-351 group (9.56) than the 7+3 group (5.95). Also, those who had a transplant after having received CPX-351 fared much better than those who had transplant after having 7+3, Dr Stone said.

“Perhaps, due to the fact that CPX-351 led to remissions at a lower level disease burden,” Dr Stone said.

On the topic of FLT3 AML, Dr Stone said patients can benefit from the addition of midostaurin, which, based on a recent trial, showed significant improvement in survival.

In an effort to improve upon midostaurin as a FLT3 inhibitor by adding gilteritinib to chemotherapy, Dr Stone said there are a number of randomized trials comparing gilteritinib plus chemotherapy to midostaurin plus chemotherapy, and prenolin plus chemotherapy to midostaurin plus chemotherapy.

The treatments may also be improved upon by adding BCL-2 inhibitor venetoclax, Dr Stone said, noting a phase 1 study on the maximal tolerated dose of venetoclax in combination with daunorubicin/cytarabine induction in previously untreated adults with AML. The complete response (CR) rate for the first 13 patients was 11/13. Of the 11 CRs, minimal residual disease (MRD) was measured by flow cytometry in 9. Seven of 9 were MRD negative at CR.

Looking at uncontrolled data of azacitidine and venetoclax, and decitabine and venetoclax, in AML patients who were not deemed fit for chemotherapy, there was a much higher response rate among all genetic subtypes than what would be expected with azacitidine and venetoclax or azacitidine alone, Dr Stone said.

The VIALE-A randomized trial, published last summer by Dr Courtney DiNardo and colleagues, compared venetoclax and azacitidine to placebo and azacitidine in patients that were either 75 years of age or older, or between 18-74 years of age with at least 1 significant comorbidity, such as CHF. This trial showed that there was a significant improvement in survival for patients who received venetoclax rather than placebo, with a nice reduction in the hazard ratio (HR 0.66, 95% CI, 0.52-0.85, P=.001) indicating better outcomes with azacitidine and venetoclax.

However, Dr Stone said, not all patients benefitted equally from the combination compared to azacitidine alone. Those patients were under 75 years of age with significant comorbidities, and did not benefit that much from adding venetoclax to azacitidine. But, almost all genetic subtypes did, especially those with the molecular markers IDH1 and IDH2.

Looking at oral azacitidine in the post-remission setting, Dr Stone said it causes a number of biochemical changes in the cell including DNA hypomethylation, DNA damage and RNA disruption.

The QUAZAR AML-001 study took patients who were 55 or older who got intensive chemotherapy with either 1 or 2 cycles of the consolidation, but were not going to have a stem cell transplant; have intermediate- or poor-risk cytogenetics; and were not candidates for HSCT. Patients either received placebo (n=234) for 14 days or oral azacitidine (n=238) for 14 days every month, and kept receiving it until they relapsed.

“Patients who were randomized to receive the oral azacitidine enjoyed a superior overall and relapse-free survival. So, that was quite exciting. The problem is how many patients are there who are 55 or greater who get intensive chemotherapy, but who aren’t going to get the stem cell transplant. Nonetheless, this is a very important study,” Dr Stone said.

Dr Stone finished up with relapsed AML. The treatment goal in general, he said, is to induce the second remission then perform an allogeneic stem cell transplant.

There are a variety of new treatment options for relapsed AML, including enasidenib for the IDH2 mutation, ivosidenib for IDH1, and gilteritinib for FLT3.

There are a lot of new ideas, but in the phase 3 ADMIRAL trial for R/R mutant FLT3 AML, gilteritinib “beat” salvage chemotherapy in the post-remission setting leading to superior median overall survival, Dr Stone said. However, when adding venetoclax to gilteritinib, there is a very impressive response rate, although there’s a lot of mild suppression. The response rate was quite high (86%, n=41) overall, as well as in the prior FTL3 TKI exposure group (82%, n = 28). Although the median survival was relatively short, the survival appears to be good for those with the ITD subtype of FLT3.

In terms of venetoclax in combination with FLAG-IDA in R/R AML, Dr Stone mentioned a Phase 1b/2 trial led by Dr DiNardo on venetoclax in combination with AML induction/consolidation therapy with FLAG-IDA in patients with newly diagnosed R/R AML.

Dr Stone said what needed to be done was decrease venetoclax from the original 21-day dosing to 14 days as well as regulate cytarabine from 2 gm/m2 to 1.5gm/m2. The overall response rate in this trial was good (82%, n = 56), he said. There was high composite CR (76%, n = 52) as well. Overall, survival was good with some drop off in the R/R patient. However, mutated FLT3-AML did not do as well.

“The problem of what to do with mutant FLT3 AML in the upfront and relapse setting remains … an unanswered question.”

Dr Stone said he hopes certain molecules will afford help for FLT3 AML, such as APR-246, a so-called p53 refolding agent; anti-CD47 antibody (5F9); or anti-CD70 antibody. In turn, Dr Stone referenced a Phase 1b study showing how effective the anti-CD47 antibody magrolimab combined with azacitidine is in AML patients.

The trial provided patients with a magrolimab priming dose of 1mg/kg, necessary, Dr Stone said, because of the expression of CD47 on the surface of red cells, and a dose ramp-up was utilized to mitigate on-target anemia. Most patients received magrolimab 30 mg/kg weekly or every other week along with a standard dose of azacitidine. The ORR was good (63%, n = 27) as well as the CR rate (42%, n = 18), with similar responses in TP53-mutant patients. In all, magrolimab plus azacitidine efficacy compared favorably to azacitidine monotherapy (CR rate 18-20%). The median OS was 18.9 months in TP53 wild-type patients and 12.9 months in the TP53-mutant patients.

“This is a very promising combination,” he said.

In conclusion, Dr Stone said, most patients with AML are high-risk. However, there are new treatment options for inductions, including CPX-351, midostaurin, and azacitidine/venetoclax; maintenance, including oral azacitidine; and relapse, including gilteritinib. There are also a number of new combinations on the way, including venetoclax and gilteritinib, he said.—Emily Bader